The overall hypothesis to be tested is that Twist is involved in negative regulation of myogenesis by interfering with required transcriptional coregulators, in particular p300 and/or PCAF, and by interacting with other regulators of early myogenic differentiation, such as Msx. This hypothesis will be tested by molecular genetic as well as biochemical analysis of a) mechanisms by which mouse Twist influences the transcription activation, by MEF2 and bHLH proteins of the different steps that eventually lead to the myogenic phenotype; b) the role of p300 and PCAF in this process; c) the interaction between Twist and Msx proteins; and d) a search for the existence and role of muscle restricted partners of p300, P/CAF and Twist. The isolation of co-regulators of muscle regulatory genes and understanding the roles of these molecules will be valuable toward our eventual goal, the development of preventive and therapeutic approaches to early diagnosis and intervention of craniofacial malformation and dygenesis.